The present invention relates to new peptide compounds that are analogues of Glucagon-Like Peptide-1 (7-37).
The Glucagon-Like Peptides-1 (7-37) and (7-36) NH2 (tGLP-1) are peptides of intestinal origin that are heavily involved in the control of glucidic homeostasis. These peptides are the principal mediators of the xe2x80x9centero-insular axisxe2x80x9d and act by bindings to specific receptors.
tGLP-1 is predominantly active in the pancreas where it exerts a powerful stimulating effect on the secretion of insulin by xcex2 cells in a glucose-dependent manner (S. Mojsov et al., J. Clin. Invest., 1987, 79, 619; and J. J. Hoist, F.E.B.S. Letters, 1987, 211, 169). That stimulation is accompanied by stimulation of the release of somatostatin and inhibition of the release of glucagon.
In parallel with the above-mentioned effects on the pancreas, tGLP-1 retards gastric emptying, reduces acid secretions and stimulates the peripheral utilisation of glucose in the muscles, liver and adipocytes. (M. L. Villanueva et al., Diabetologia, 1994, 37, 1163; D. J. Drucker, Diabetes, 1998, 47, 159).
Recent studies have also demonstrated that tGLP-1 could have an effect on eating behaviour by inhibiting food and drink intake as a result of action on the satiety centres (M. D. Turton et al., Nature. 1996, 379, 69).
tGLP-1 thus has many potential therapeutic applications, especially in the treatment of non-insulin-dependent type II diabetes, obesity, and type I diabetes. Like many hormonal peptides, however, it has a rather short plasma half-lifexe2x80x94less than 2 minutes (T. J. Kieffer et al., Endocrinology, 1995, 136, 3585)xe2x80x94which limits its use.
The use of the natural peptide GLP1 (7-37) for its insulinotropic properties has been described extensively, whether as the natural peptide GLP1 (7-37) or GLP1 (7-36) NH2 on its own, in the form of salts, esters or amides (U.S. Pat. No. 5,616,492, WO 8706941, WO 9011 296), associated with phospholipids (WO 9318785) or associated with other hypoglycaeinic substances (WO 9318786). Analogues modified at some positions of the natural sequence have also been studied (EP 733 644, EP 708 179, EP 658 568, WO 91 11457) with the aim of devising compounds as potent as GLP1 (7-37) that are better absorbed.
The compounds of the present invention have a novel structure derived from that of tGLP-1 by modifications to several residues and/or by suppression of arginine at position 36. In addition to the fact that they are new, these compounds have valuable pharmacological properties as a result of their agonist character in relation to tGLP-1 receptors. The modifications have the additional advantage of substantially increasing the metabolic stability of the compounds of the invention, thus giving them a duration of action superior to that of the natural peptide. Those properties make the compounds especially valuable in the treatment of pathologies in which tGLP-1 is involved, especially in the treatment of non-insulin-dependent type II diabetes, obesity, and type I diabetes.
The present invention relates to peptide compounds of the general formula (I):
Z1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-X4-X5-Ser-X6-X7-X8-Glu-Gly-Gln-Ala-X9-Lys-X10-X11-X12-Ala-X13-X14-Val-Lys-Gly-X15-Gly-Z2 SEQ ID NO: 1xe2x80x83xe2x80x83(I)
wherein:
Z1, substituent of the terminal amino group of the peptide of formula (I), represents a hydrogen atom, an alkyl group, a linear or branched (C1-C6)-acyl group, or an optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylalkylcarbonyl, optionally substituted heteroarylalkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkoxycarbonyl or optionally substituted alkoxycarbonyl group,
Z2, substituent of the terminal carbonyl group of the peptide of formula (I), represents a hydroxy group, a linear or branched (C1-C6)-alkoxy group, or an amino group optionally substituted by one or two identical or different groups selected from linear or branched (C1-C6)-alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylalkylcarbonyl and optionally substituted heteroarylalkylcarbonyl, or by two groups that together with the nitrogen atom form a saturated ring having from 5 to 7 ring members),
X1 to X14 each represents, independently of the others:
a natural or non-natural amino acid residue, having the D or L configuration, of the formula: 
xe2x80x83wherein:
R1 represents a hydrogen atom and R2 represents a hydrogen atom or an alkyl, aminoalkyl (optionally substituted on the nitrogen atom by one or two alkyl, phenyl, benzyl, cycloalkyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkoxycarbonyl and/or optionally substituted alkoxycarbonyl groups), thioalkyl (optionally substituted on the sulphur atom by an alkyl, phenyl, benzyl or cycloalknyl group), hydroxyalkyl (optionally substituted on the oxygen atom by an alkyl, phenyl, benzyl or cycloalkyl group), carboxyalkyl, carbamoylalkyl, guanidinoalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted fused cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
or R1 and R2 together with the carbon atom carrying them, form a cycloalkyl or fused cycloalkyl group,
or a natural or non-natural cyclic amino acid residue, having the D or L configuration, of the formula: 
xe2x80x83wherein A, together with the nitrogen and carbon atoms to which it is attached, forms a mono- or bi-cyclic group having from 5 to 11 ring members which is saturated, partially unsaturated or unsaturated, and is optionally substituted,
or a 3-amino-3-(2-furyl)propanoic acid residue, and
X15 represents a bond or an arginine residue (Arg),
and addition salts thereof with a pharmaceutically acceptable acid or base.
with the proviso that:
X15 represents a bond:
when X1 is a residue having the L or D configuration selected from tyrosine (Tyr), arginine (Arg), phenylalanine (Phe), ornithine (Orn), methionine (Met), proline (Pro), leucine (Leu), valine (Val), isoleucine (Ile), alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gln) and histidine (His),
and/or
when X2 represents a residue having the L or D configuration selected from serine (Ser), glycine (Gly), cysteine (Cys), sarcosine (Sar), alanine (Ala), proline (Pro), valine (Val), leucine (Leu), isoleucine (Ile) and threonine (Thr),
and/or
when X3 represents an amino acid residue having the L or D configuration selected from glutamine (Gln), aspartic acid (Asp), threonine (Thr), asparagine (Asn) and glutamic acid (Glu),
and/or
when X5 represents a tyrosine residue (Tyr),
and/or
when X6 represents a lysine residue (Lys),
and/or
when X10 represents an amino acid residue selected from glutamine (Gln), alanine (Ala), threonine (Thr), serine (Ser) and glycine (Gly),
and/or
when X13 represents an amino acid residue selected from phenylalanine (Phe), valine (Val), leucine (Leu), isoleucine (Ile), alanine (Ala) and tyrosine (Tyr),
it being understood that:
the residues X1 to X15 may not be so selected that the peptide obtained is identical to the natural peptide,
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated cyclic hydrocarbon group having from 3 to 8 ring members,
the expression xe2x80x9cfused cycloalkylxe2x80x9d denotes a bicyclic group having from 8 to 11 ring members composed of a saturated carbon-containing rings fused with a saturated or unsaturated ring optionally comprising one or two hetero atoms selected from nitrogen, oxygen and sulphur, for example an indan, tetrahydronaphthalene or tetrahydroquinoline group,
the term xe2x80x9carylxe2x80x9d denotes a phenyl, naphthyl or biphenyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes a mono- or bi-cyclic group having from 5 to 11 ring members and containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, for example a furyl, pyridyl, thienyl or indolyl group,
the term xe2x80x9carylcarbonylxe2x80x9d denotes an Raxe2x80x94COxe2x80x94 group, the term xe2x80x9carylalkylcarbonylxe2x80x9d denotes and Raxe2x80x94Rbxe2x80x94COxe2x80x94 group, the term xe2x80x9cheteroarylcarbonylxe2x80x9d denotes an Rcxe2x80x94COxe2x80x94 group and the term xe2x80x9cheteroarylalkylcarbonylxe2x80x9d denotes an Rcxe2x80x94Rbxe2x80x94COxe2x80x94 group, the term xe2x80x9caryloxycarbonylxe2x80x9d denotes an Raxe2x80x94Oxe2x80x94COxe2x80x94 group, the term xe2x80x9carylalkoxycarbonylxe2x80x9d denotes an Raxe2x80x94Rbxe2x80x94Oxe2x80x94COxe2x80x94 group and the term xe2x80x9calkoxycarbonylxe2x80x9d denotes an Rbxe2x80x94Oxe2x80x94COxe2x80x94 group, in which groups Ra represents an aryl group as defined hereinabove, Rb represents an alkyl group as defined hereinabove and Rc represents a heteroaryl group as defined hereinabove,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms defined above denotes that the groups in question are substituted by one or more halogen atoms or linear or branched (C1-C6)-alkyl, hydroxy, linear or branched (C1-C6)-alkoxy, amino, cyano, nitro or linear or branched (C1-C6)-perhaloalkyl groups,
each peptide bond xe2x80x94COxe2x80x94NHxe2x80x94 may optionally be replaced by a pseudopeptide bond selected from xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94COxe2x80x94CH2xe2x80x94NHxe2x80x94.
Among the pharmaceutically acceptable acids there may be mentioned hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc. The present invention relates especially to peptide compounds of formula (I) wherein the residues X1 to X14 are selected as a function of the nature of their side chain, which may be of aromatic character or of aliphatic character, may be capable of establishin interactions of the hydrogen bonding type or capable of establishing ionic interactions, or may be of cyclic nature.
The natural or non-natural amino acid residues having the D or L configuration that have a side chain of aromatic character are represented by the following formula: 
wherein:
R1a represents a hydrogen atom and R2a represents a cycloalkyl group fused with an unsaturated ring as defined hereinabove, and optionally substituted, or an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group, among which residues having a side chain of aromatic character there may be mentioned more specifically the phenylalanine (Phe), histidine (His), tyrosine (Tyr), tryptophan (Trp), homophenylalanine (Hof), halophenylalanine (for example 4-chlorophenylalanine (4-Cl-Phe)), dihalophenylalanine (for example 3,4-dichlorophenylalanine (3,4-di-Cl-Phe)), alkylphenylalanine (for example 4-methylphenylalanine (4-Me-Phe)), nitrophenylalanine (for example 4-nitrophenylalanine (4-NO2-Phe)), 3-pyridylalanine (3-Pya), 2-thienylalanine (Tha), 2-furylalanine (Fua), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), phenylglycine (Phg) and 3-nitrotyrosine (3-NO2-Tyr) residues,
The natural or non-natural amino acid residues having the D or L configuration that have a side chain of aliphatic character are represented by the following formula: 
xe2x80x83wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
The natural or non-natural amino acid residues having the D or L configuration that have a side chain capable of establishing interactions of the hydrogen bonding type are represented by the formula: 
xe2x80x83wherein:
R1c represents a hydrogen atom and R2c represents an aminoalkyl (optionally substituted on the nitrogen atom by an alkyl, phenyl, benzyl or cycloalkyl group), thioalkyl (optionally substituted on the sulphur atom by an alkyl, phenyl, benzyl or cycloalkyl group), hydroxyalkyl (optionally substituted on the oxygen atom by an alkyl, phenyl, benzyl or cycloalkyl group), carboxyalkyl, carbamoylalkyl or guanidinoalkyl group,
among which residues there may be mentioned more specifically the methionine (Met), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), tryptophan (Trp), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and benzylcysteine (Bcy) residues,
The natural or non-natural amino acid residues having the D or L configuration that have a side chain capable of establishing interactions of the ionic type are represented by the formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
The non-natural amino acid residues having the D or L configuration that have a side chain of cyclic nature are represented by the following formula: 
xe2x80x83wherein:
R1c and R2c together form a cycloalkyl or a fused cycloalkyl group,
among which residues there may be mentioned more specifically the 1-amino-1-cyclohexanecarboxylic acid (Acy), 2-aminoindan-2-carboxylic acid (Aic) and 2-aminotetraline-2-carboxylic acid (Atc) residues,
X1 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aromatic character, represented by the formula (a),
X2 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X3 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
X4 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
or a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X5 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X6 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
X7 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
or a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X8 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X9 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X10 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
or a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X11 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aromatic character, represented by the formula (a),
X12 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions, represented by the formula (d),
or a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X13 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aromatic character, represented by the formula (a),
X14 preferably represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character, represented by the formula (b),
X15 preferably represents a bond.
Preferably, in compounds of formula (I) Z1 represents a hydrogen atom.
In compounds of formula (I), Z2 preferably represents a group selected from hydroxy, linear or branched (C1-C6)-alkoxy, and amino. More specifically, Z2 represents an amino group.
An advantageous aspect of the invention concerns compounds of formula (I) wherein:
Z1 represents a hydrogen atom,
Z2 represents a group selected from hydroxy, linear or branched (C1-C6)-alkoxy, and amino,
X1 and X11 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues having a side chain of aromatic character represented by the following formula: 
xe2x80x83wherein:
R1a represents a hydrogen atom and R2a represents a cycloalkyl group fused with an unsaturated ring as defined hereinabove, and optionally substituted, or an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
among which residues having a side chain of aromatic character there may be mentioned more specifically the phenylalanine (Phe), histidine (His), tyrosine (Tyr), tryptophan (Trp), homophenylalanine (Hof), halophenylalanine (for example 4-chlorophenylalanine (4-Cl-Phe)), dihalophenylalanine (for example 3,4-dichlorophenylalanine (3,4-di-Cl-Phe)), alkylphenylalanine (for example 4-methylphenylalanine (4-Me-Phe)), nitrophenylalanine (for example 4-nitrophenylalanine (4-NO2-Phe)), 3-pyridylalanine (3-Pya), 2-thienylalanine (Tha), 2-furylalanine (Fua), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), phenylglycine (Phg) and 3-nitrotyrosine (3-NO2-Tyr) residues,
X2 and X9 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues having a side chain of aliphatic character represented by the following formula: 
xe2x80x83wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
X5 and X6 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues that have a side chain capable of establishing ionic interactions represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
X4, X7, X10 and X12 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues that have a side chain capable of establishing ionic interactions represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
or are independently selected from the natural or non-natural amino acid residues having a side chain of aliphatic character represented by the following formula: 
wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
X5 represents a valine residue (Val),
X8 and X14 independently represent a leucine residue (Leu) having the D or L configuration,
X13 represents a tryptophan residue (Trp), and
X15 represents a bond or an arginine residue (Arg),
and addition salts thereof with a pharmaceutically acceptable acid or base.
Another advantageous aspect of the invention concerns the compounds of formula (I) wherein:
Z1 represents a hydrogen atom.
Z2 represents a group selected from hydroxy, linear or branched (C1-C6)-alkoxy, and amino,
X1 and X11 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues having a side chain of aromatic character represented by the following formula: 
xe2x80x83wherein:
R1a represents a hydrogen atom and R2a represents a cycloalkyl group fused with an unsaturated ring as defined hereinabove, and optionally substituted, or an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
among, which residues having a side chain of aromatic character there may be mentioned more specifically the phenylalanine (Phe), histidine (His), tyrosine (Tyr), trptophan (Trp), homophenylalanine (Hof), halophenylalanine (for example 4-chlorophenylalanine (4-Cl-Phe)), dihalophenylalanine (for example 3,4-dichlorophenylalanine (4-di-Cl-Phe)), alkylphenylalanine (for example 4-methylphenylalanine (4-Me-Phe)), nitrophenylalanine (for example 4-nitrophenylalanine (4-NO-Phe)), 3-pyridylalanine (3-Pya), 2-thienylalanine (Tha), 2-furylalanine (Fua), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), phenylglycine (Phg) and 3-nitrotyrosine (3-NO2-Tyr) residues,
X2 and X9 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues having a side chain of aliphatic character represented by the following formula: 
xe2x80x83wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
X3 and X6 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues that have a side chain capable of establishing ionic interactions represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
X4, X7 and X10 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues that have a side chain capable of establishing ionic interactions represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
X5 represents a valine residue (Val),
X8 and X14 independently represent a leucine residue (Leu) having the D or L configuration,
X12 represents a natural or non-natural amino acid residue having the D or L configuration, and is selected from the amino acid residues having a side chain of aliphatic character represented by the following formula: 
xe2x80x83wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
X13 represents a tryptophan residue (Trp),
X15 represents a bond or an arginine residue (Arg),
and addition salts thereof with a pharmaceutically acceptable acid or base.
Another advantageous aspect of the invention concerns the compounds of formula (I) wherein:
Z1 represents a hydrogen atom,
Z2 represents a group selected from hydroxy, linear or branched (C1-C6)-alkoxy, and amino,
X1 and X11 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues having a side chain of aromatic character represented by the following formula: 
xe2x80x83wherein:
R1a represents a hydrogen atom and R2 represents a cycloalkyl group fused with an unsaturated ring as defined hereinabove, and optionally substituted, or an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
among which residues having a side chain of aromatic character there may be mentioned more specifically the phenylalanine (Phe), histidine (His), tyrosine (Tyr), tryptophan (Trp), homophenylalanine (Hof), halophenylalanine (for example 4-chlorophenylalanine (4-Cl-Phe)), dihalophenylalanine (for example 3,4-dichlorophenylalanine (3,4-di-Cl-Phe)), alkylphenylalanine (for example 4-methylphenylalanine (4-Me-Phe)), nitrophenylalanine (for example 4-nitrophenylalanine (4-NO2-Phe)), 3-pyridylalanine (3-Pya), 2-thienylalanine (Tha), 2-furylalanine (Fua), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), phenylglycine (Phg) and 3-nitrotyrosine (3-NO2-Tyr) residues,
X2 and X9 independently represent an alanine residue (Ala) having the D or L configuration,
X3 and X6 represent a natural or non-natural amino acid residue having the D or L configuration and are independently selected from the amino acid residues that have a side chain capable of establishing ionic interactions represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
X4 represents an aspartic acid residue (Asp),
X5 represents a valine residue (Val),
X7 represents a tyrosine residue (Tyr),
X8 and X14 independently represent a leucine residue (Leu) having the D or L, configuration,
X10 represents a glutamine residue (Glu),
X12 represents an isoleucine residue (Ile),
X13 represents a tryptophan residue (Trp),
X15 represents a bond or an arginine residue (Arg),
and addition salts thereof with a pharmaceutically acceptable acid or base.
The present invention relates more especially to the peptide compounds of formula (II):
Z1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-X15-Gly-Z2 SEQ ID NO: 2xe2x80x83xe2x80x83(II)
wherein:
Z1 represents a hydrogen atom,
Z2 represents a group selected from hydroxy, linear or branched (C1-C6)-alkoxy, and amino,
X1 represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aromatic character and is represented by the following formula: 
xe2x80x83wherein:
R1a represents a hydrogen atom and R2a represents a cycloalkyl group fused with an unsaturated ring as defined hereinabove, and optionally substituted, or an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
among which residues having a side chain of aromatic character there may be mentioned more specifically the phenylalanine (Phe), histidine (His), tyrosine (Tyr), tryptophan (Trp), homophenylalanine (Hof), halophenylalanine (for example 4-chlorophenylalanine (4-Cl-Phe)), dihalophenylalanine (for example 3,4-dichlorophenylalanine (3,4-di-Cl-Phe)), alkylphenylalanine (for example 4-methylphenylalanine (4-Me-Phe)), nitrophenylalanine (for example 4-nitrophenylalanine (4-NO2-Phe)), 3-pyridylalanine (3-Pya), 2-thienylalanine (Tha), 2-furylalanine (Fua), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), phenylglycine (Phg) and 3-nitrotyrosine (3-NO2-Tyr) residues,
X2 represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain of aliphatic character and is represented by the following formula: 
xe2x80x83wherein:
R1b represents a hydrogen atom and R2b represents a hydrogen atom or an alkyl or cycloalkyl group,
among which residues there may be mentioned more specifically the glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), 2-aminobutyric acid (Abu), 2-aminoisobutyric acid (Aib), xcex2-cyclohexylalanine (Cha), homoleucine (Hol), norleucine (Nle), norvaline (Nva) and tert-leucine (Tle) residues,
X3 represents a natural or non-natural amino acid residue having the D or L configuration that has a side chain capable of establishing ionic interactions and is represented by the following formula: 
xe2x80x83wherein:
R1d represents a hydrogen atom and R2d represents an aminoalkyl, thioalkyl, hydroxyalkyl, carboxyalkyl, guanidinoalkyl, imidazolyl or imidazolylalkyl group,
among which residues there may be mentioned more specifically the aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), diaminoacetic acid (NH-Gly), diaminobutyric acid (Dab), diaminopropionic acid (Dapa), ornithine (Orn) and methionine (Met) residues,
X15 represents a bond or an arginine residue, it being understood that the restrictions relating to the compounds defined in formula (I) apply to the compounds of formula (II).
More specifically, in the compounds of formula (II) X15 represents a bond.
Amongst the compounds of formula (II), the compounds wherein X2 represents an alanine residue (Ala) having the D or L configuration and X15 represents a bond are preferred.
Amongst the preferred compounds of the invention there may be mentioned more especially the following peptides:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-(D)-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 3
Trp-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-(D)-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 4
Trp-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 5
His-Ala-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Val-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 6
His-Ala-His-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Val-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 7
His-Ala-(D)-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 8
His-(D)-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 9
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 10
His-Leu-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 11
His-Val-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 12
Afp-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 13
His-Ala-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 14
His-Ala-Ser-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 15
His-Ala-Lys-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 16
Phe-(D)-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Lys-Tyr-Leu-Glu-Gly-Gln-Ala-Val-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 17
Phe-(D)-Ala-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Val-(D)-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 18
His-Ala-Leu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 19
His-Ala-Met-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 20
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Trp-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 21
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Ile-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 22
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Val-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 23
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-His-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 24
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Asp-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 25
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Leu-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 26
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Val-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 27
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Tyr-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 28
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Arg-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 29
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Glu-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 30
Phe-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-NH2 SEQ ID NO: 31
His-Ala-Lys-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 32
His-Ala-Met-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 33
His-Ala-Leu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 34
His-Ala-Ser-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 35
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-(D)-Leu-Val-Lys-Gly-Arg-Gly-NH2 SEQ ID NO: 36.
The invention extends also to a process for the preparation of the compounds of formula (I) which may be obtained by various methods, such as solid phase sequential synthesis, synthesis and coupling of fragments in solution, enzymatic synthesis, or by employing molecular biology techniques.
The general methods of solid phase peptide synthesis have been described by, B. W. Erickson and R. B. Merrifield (xe2x80x9cThe Proteinsxe2x80x9d, Solid Phase Peptide Synthesis, 3rd edition, 1976, 257).
Solid phase synthesis is carried out using an automatic device which executes in a repetitive and programmable manner the cycles of deprotection, coupling and washing necessary for the sequential introduction of amino acids into the peptide chain.
The C-terminal amino acid is fixed on a resin conventionally used for the preparation of polypeptides, preferably a polystyrene crosslinked with 0.5 to 3.0% divinylbenzene and provided with activated radicals that enable the first amino acid to be fixed covalently to the resin. Appropriate selection of the resin allows the formation after synthesis of a C-terminal carboxylic acid, amide, alcohol or ester function.
The amino acids are then introduced one by one in the order determined by the operator. Each cycle of synthesis corresponding to the introduction of an amino acid comprises N-terminal deprotection of the peptide chain, successive washings designed to remove the reagents or swell the resin, coupling with activation of the amino acid and further washings. Each of those operations is followed by filtration effected as a result of the presence of a sintered glass filter incorporated in the reactor in which the synthesis is beings carried out.
The couplings reagents used are the conventional reagents for peptide synthesis, such as dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) or benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or also diphenyl-phosphorylazide (DPPA).
Activation by the formation of mixed or symmetrical anhydrides is also possible.
Each amino acid is introduced into the reactor in an approximately 6-fold excess in relation to the degree of substitution of the resin and in an approximately equivalent amount in relation to the coupling agents. The coupling reaction may be confirmed at each stage of the synthesis by the ninhydrin reaction test described by E. KAISER et al. (Anal. Biochem., 34, 595, 1970).
After assembling the peptide chain on the resin, an appropriate treatment, for example using a strong acid such as trifluoroacetic acid, or hydrofluoric acid in the presence of anisole, ethanedithiol or 2-methylindole, is used to separate the peptide from the resin and also to free the peptide of its protecting groups. The compound is then purified by conventional purification techniques, especially chromatography techniques.
The peptides of the present invention may also be obtained by coupling in solution selectively protected peptide fragments which may themselves be prepared either in the solid phase or in solution. The use of protecting groups and the exploitation of their differences in stability is analogous to solid phase methods with the exception of the attachment of the peptide chain to the resin. The C-terminal carboxy group is protected, for example, by a methyl ester or an amide function. The methods of activation during coupling are likewise analogous to those employed in solid phase synthesis.
The peptides of the present invention may also be obtained using molecular biology techniques, employing nucleic acid sequences that encode those peptides. Those sequences may be RNA or DNA and may be associated with control sequences and/or inserted into vectors. The latter are then transfected into host cells, for example bacteria. The preparation of the vectors and their production or expression in a host are carried out by conventional molecular biology and genetic engineering techniques.
The synthesis of peptides containing pseudopeptide bonds is carried out either by methods in solution or in combination with solid phase synthesis using conventional methods of organic chemistry. Thus, for example, the introduction of the xe2x80x94CH2xe2x80x94NH bond is effected by preparing Fmoc-NHxe2x80x94CHRxe2x80x94CHO aldehyde in solution according to the technique described by FEHRENTZ and CASTRO (Synthesis, 676-678, 1983) and condensing it with the growing peptide chain either in solid phase according to the technique described by SASAKl and COY (Peptides, 8, 119-121, 1988) or in solution.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of the general formula (I) or an addition salt thereof with a pharmaceutically acceptable acid or base, on its own or in combination with one or more inert, non-toxic excipients or carriers.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, sachets, paquets, soft gelatin capsules, suppositories, creams, ointments, dermal gels, transdermal devices, aerosols, drinkable and injectable ampoules.
The dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration.
The latter may be oral (including the inhalation, gingival and sublingual routes), nasal, rectal, parenteral or transdermal. Generally, the dosage ranges from 10 xcexcg to 500 mg for a treatment of one or more administrations per 24 hours, depending on the administration route and the galenic form used.